Drug Induced Nutrient Depletions:

The Truth about Common

Cardiovascular Medications
By Alan C. Simon R.Ph.
Classes of Cardiovascular Drugs
3. Anticoagulants
40. Aspirin
44. Inotropic Agents
49. Calcium Channel Blocking Agents
53. Vasodilators
57. Diuretics
69. Antiadrenergics/Sympatholytic Agents (Beta
blockers)
73. Renin Angiotensin System Antagonist (ACE
Inhibitors/ Angiotensin II)
79. Antihyperlipidemic Agents
2
Anticoagulants-
WARFARIN (COUMADIN) (Vitamin K Antagonist)
Action: Blocks the action of vitamin k (inhibits the synthesis of vitamin k-
dependent clotting factors).
Indications: Atrial fibrillation, artificial heart valves, deep venous
thrombosis, pulmonary embolism, myocardial infarction.
Dosing: Has a narrow therapeutic index, blood test are needed for dosing,
prothrombin time and INR (international normalized ratio).
Side Effects: Purple toes or fingers, skin changes, discoloration on the body,
abdominal pain, dark urine jaundice, dark urine, blood in urine, jaundice,
black, bloody, tarry stools, nose bleeds, bleeding gums, sudden headache,
vasculitis, hypotension, dizziness, paresthesia, hair loss, itching, rash, nausea,
vomiting, diarrhea.
Contraindications: Pregnancy, breast feeding, blood dyscrasias, bleeding
tendencies, senility, alcoholism, psychosis.
Warnings/Precautions: Hemorrhage, necrosis, gangrene, purple toe
syndrome, hepatic or renal insufficiency, severe to moderate hypertension,
drug to drug interactions.
3
Anticoagulants-
WARFARIN (COUMADIN) (Vitamin K Antagonist)
Nutrient depletions
Vitamin K
Interferes with the enzyme responsible for the
synthesis of vitamin K (Matrix Gla protein)
1. Bell RG, Metabolism of vitamin K and prothrombin synthesis:
anticoagulants and the vitamin K-epoxide cycle, Fed Proc. 1978
Oct; 37(12): 2599-604.
4
5
The following factors, alone or in combination, may be
responsible for INCREASED PT/INR response:
ENDOGENOUS FACTORS:
blood dyscrasias
See CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency
6
The following factors, alone or in combination, may be
responsible for DECREASED PT/INR response:
ENDOGENOUS FACTORS:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome
7
Potential drug interactions with
COUMADIN
Classes of Drugs
Adrenal Cortical Steroid
Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics
Antibiotics
Anticonvulsants
Antidepressants
Antihistamines
Antineoplastics
Antipsychotic
Medications
Antithyroid Drugs
Barbiturates
Diuretics
Enteral Nutritional
Supplements
Fungal Medications,
Systemic
Gastric Acidity and
Peptic Ulcer Agents
Hypnotics
Hypolipidemics
Bile Acid-Binding Resins
HMG-CoA Reductase
Inhibitors
Immunosuppressives
Oral Contraceptives,
Estrogen Containing
Selective Estrogen
Receptor
Modulators
Steroids, Adrenocortical
Tuberculosis Agents
Vitamins
8
Potential drug interactions with
COUMADIN
Classes of Drugs
alcohol
aminoglutethimide
amobarbital
atorvastatin
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate
chlordiazepoxide
chlorthalidone
cholestyramine
clozapine
corticotropin
cortisone
cyclophosphamide
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole
moricizine
hydrochloride
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin
pravastatin
prednisone
primidone
propylthiouracil
raloxifene
ranitidine
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
9
Botanical (Herbal) Medicines And
Warfarin (package insert)
Botanical (Herbal) Medicines: Caution should be exercised
when botanical medicines (botanicals) are taken
concomitantly with COUMADIN.
Few adequate, well-controlled studies exist evaluating the
potential for metabolic and/or pharmacologic interactions
between botanicals and COUMADIN.
Due to a lack of manufacturing standardization* with botanical
medicinal preparations, the amount of active ingredients may
vary. This could further confound the ability to assess potential
interactions and effects on anticoagulation. It is good practice
to monitor the patients response with additional PT/INR
determinations when initiating or discontinuing botanicals.
*
*There is manufacturing standardization in FDA Drug Registered
manufacturing guidelines.
10
Botanical (Herbal) Medicines And
Warfarin (package insert)
Specific botanicals reported to affect COUMADIN therapy
include the following:
Bromelain, danshen, dong quai (Angelica sinensis),
garlic, Ginkgo biloba, ginseng, and cranberry products
are associated most often with an INCREASE in the
effects of COUMADIN.
Coenzyme Q10 and St. Johns wort are associated most
often with a DECREASE in the effects of COUMADIN.
Some botanicals may cause bleeding events when taken
alone (eg, garlic and Ginkgo biloba) and may have
anticoagulant, antiplatelet, and/or fibrinolytic properties.
These effects would be expected to be additive to the
anticoagulant effects of COUMADIN. Conversely, other
botanicals may have coagulant properties when taken
alone or may decrease the effects of COUMADIN.
11
Potential interaction of Ginkgo biloba leaf with
antiplatelet or anticoagulant drugs:
what is the evidence?
Mol Nutr Food Res. 2008 Jul;52(7):764-71.
Ginkgo does not significantly impact haemostasis
nor adversely affect the safety of co-administered
aspirin or warfarin
Most of these studies were undertaken using
EGb 761, a well-defined extract of Ginkgo
biloba
Nevertheless, the possibility of an idiosyncratic
bleeding event due to Ginkgo use cannot be
excluded
PMID: 18214851
12
Effect of Ginkgo biloba (EGb 761) and aspirin on platelet
aggregation and platelet function analysis among older adults at
risk of cardiovascular disease: a randomized clinical trial.
Blood Coagul Fibrinolysis. 2007 Dec;18(8):787-93
Ginkgo biloba (EGb 761, 300 mg/day) double-blind,
placebo-controlled
a relatively high dose of Ginkgo biloba combined with
325 mg/day daily aspirin did not have a clinically or
statistically detectable impact on indices of
coagulation examined over 4 weeks, compared with
the effect of aspirin alone.
PMID: 17982321
Stanford Prevention Research Center and the Department of
Medicine, Stanford University Medical School
13
Common Botanicals- contraindicated
with Warfarin
Botanicals that contain
coumarins with potential
anticoagulant effects:
Agrimony
1
Alfalfa
Angelica (Dong Quai)
Aniseed
Arnica
Asafoetida
Bogbean
2
Boldo
Buchu
Capsicum
3
Cassia
4
Celery
Chamomile
(German and Roman)
Dandelion
4
Fenugreek
Horse Chestnut
Horseradish
Licorice
4
Meadowsweet
2
Nettle
Parsley
Passion Flower
Prickly Ash (Northern)
Quassia
Red Clover
Sweet Clover
Sweet Woodruff
Tonka Beans
Wild Carrot
Wild Lettuce
14
1 Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible vitamin K content.
2 Contains coumarins and salicylate.
3 Contains coumarins and has fibrinolytic properties.
4 Contains coumarins and has antiplatelet properties.
Common Botanicals- contraindicated
with Warfarin
Miscellaneous botanicals
with anticoagulant
properties:
Bladder Wrack (Fucus) Pau darco
15
1 Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible vitamin K content.
2 Contains coumarins and salicylate.
3 Contains coumarins and has fibrinolytic properties.
4 Contains coumarins and has antiplatelet properties.
5 Has antiplatelet and fibrinolytic properties.
Botanicals with fibrinolytic
properties:
Bromelains
Capsicum
3
Garlic
5
Ginseng (Panax)
5
Inositol Nicotinate
Onion
5
Botanicals with coagulant
properties:
Agrimony
1
Goldenseal
Mistletoe
Yarrow
Common Botanicals- contraindicated
with Warfarin
Botanicals that contain
salicylate and/or have
antiplatelet properties:
Agrimony
1
Aloe Gel
Aspen
Black Cohosh
Black Haw
Bogbean
2
Cassia
4
Clove
Dandelion
4
Feverfew
Garlic
5
German Sarsaparilla
Ginger
Ginkgo Biloba
Ginseng (Panax)
5
Licorice
4
Meadowsweet
2
Onion
5
Policosanol
Poplar
Senega
Tamarind
Willow
Wintergreen
16
1 Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible vitamin K content.
2 Contains coumarins and salicylate.
3 Contains coumarins and has fibrinolytic properties.
4 Contains coumarins and has antiplatelet properties.
5 Has antiplatelet and fibrinolytic properties.
Vitamin K- Coumadin
Package insert states:
The amount of vitamin K in food may affect
therapy with COUMADIN.
Eat a normal, balanced diet maintaining a
consistent amount of vitamin K.
Avoid drastic changes in dietary habits, such as
eating large amounts of green leafy vegetables.
You should also avoid intake of cranberry juice or
any other cranberry products.
17
Vitamin K in Foods
Beverages Portion Vitamin K content
Micrograms
Coffee brewed from grounds, prepared with
tap water
6 oz 0.2
Cola with caffeine 12 oz 0.0
Fruit punch drink with added nutrients canned 8 oz 0.0
Milk 1 cup 0.5
Tea brewed

6 oz 0.0
Water, tap 8 oz 0.0
18
Dairy Products/Eggs Portion Vitamin K content
Micrograms
Butter 1 tbsp 1.0
Cheddar cheese 1 oz 0.8
Eggs, cooked 1 large 2.6
Sour cream, cultured 1 tbsp 0.1
Yogurt plain, whole milk 8 oz 0.5
Ice cream, vanilla 1/2 cup 0.2
Vitamin K in Foods
Grains Portion Vitamin K content
Micrograms
Bagel, plain 1 (4") 1.0
Bread, assorted types 1 slice 0.8
Cereal 1/2 cup 2.1
Flour, white, wheat, all-purpose, enriched,
bleached
1 cup 0.4
Oatmeal 1 cup 7.5
Rice, white 1 cup 0.0
Spaghetti, cooked, enriched 1 cup 0.0
19
Fruits Portion Vitamin K content
Micrograms
Apple 1 3.0
Banana 1 0.6
Blueberries, raw 1 cup 28.0
Cantaloupe 1/8 melon 1.7
Grapes, red or green 10 grapes 7.3
Grapefruit 1/2 grapefruit 0.0
Lemon 1 0.0
Orange 1 0.0
Peach 1 2.5
Vitamin K in Foods
Meat Portion Vitamin K content
Micrograms
Beef 3 oz 1.9
Chicken 1 cup 4.3
Ham 2 slices 0.0
Salmon 3 oz 0.3
Pork 3 oz 0.0
Shrimp 3 oz 0.0
Tuna, light, canned in oil 3 oz 37.4
Tuna, light, canned in water 3 oz 0.2
Turkey meat only, roasted 1 cup 5.2
20
Fats and Dressings Portion Vitamin K content
Micrograms
Margarine 1 tbsp 14.5
Mayonnaise 1 tbsp 5.8
Oils
Soybean 1 tbsp 3.4
Olive 1 tbsp 8.1
Corn 1 tbsp 0.3
Peanut 1 tbsp 0.1
Safflower 1 tbsp 1.0
Sesame 1 tbsp 1.8
Sunflower 1 tbsp 0.7
Vitamin K in Foods
Vegetables Portion Vitamin K content (mcg)
Asparagus, frozen, cooked 1 cup 144.0
Avocado 1 oz 6.0
Beans, green 1 cup 20.0
Broccoli, cooked 1 cup 220.1
Brussels sprouts, cooked 1 cup 218.9
Cabbage, raw 1 cup 53.2
Carrots 1 cup 21.4
Cauliflower, boiled 1 cup 17.1
Celery 1 cup 56.7
Collard greens 1 cup 1059.4
Corn 1 cup 0.5
Cucumber, peel removed 1 cup 8.6
Eggplant, cooked 1 cup 2.9
Endive, raw 1 cup 115.5
Kale, cooked 1 cup 1146.6
Lettuce, romaine or green leaf, raw 1 cup 97.2
Lettuce, iceberg, raw 1 cup 13.3
Mushrooms 1 cup 0.2
Mustard greens, cooked 1 cup 419.3
Parsley 10 sprigs 164.0
Peas, cooked 1 cup 48.3
Pepper, green, raw 1 cup 11.0
Potato, baked 1 4.0
Pumpkin, boiled, drained, no salt 1 cup 2.0
Sauerkraut, canned 1 cup 30.7
Spinach, cooked 1 cup 1027.3
Spinach, raw leaf 1 cup 144.9
Spring onion or scallion, raw 1 cup 207.0
Tomato 1 9.7
Turnip greens, boiled, drained, no salt 1 cup 529.3
Watercress, raw 1 cup 85.0
21
Vitamin K in Foods
Condiments and
Sweeteners
Portion Vitamin K content (mcg)
Gelatin 1/2 cup 0.0
Honey 1 tbsp 0.0
Peanut butter 2 tbsp 0.2
Pickle, dill 1 pickle 25.4
Sugar, white, granulated 1 tsp 0.0
22
Warfarin use and the risk of valvular
calcification.
Thromb Haemost. 2009 Dec;7(12):2023-7.
Warfarin affects the synthesis and function of the matrix
Gla-protein, a vitamin K-dependent protein, which is a
potent inhibitor of tissue calcification.
RESULTS: significant association between the use of warfarin
and the risk of calcification
473 of 725 patients (65%) on warfarin vs. 225 of 430
patients (52%) not on warfarin.
CONCLUSIONS: Use of warfarin in patients with AF is
associated with an increased prevalence of mitral or aortic
valve calcium.
PMID: 19793187
23
Relation of circulating Matrix Gla-Protein and
anticoagulation status in patients with aortic valve
calcification.
Thromb Haemost. 2009 Apr;101(4):706-13
Matrix-Gla Protein (MGP) is a vitamin K-dependent protein
acting as a local inhibitor of vascular calcification.
Vitamin K-antagonists (oral anticoagulant; OAC) inhibit the
activation of MGP by blocking vitamin K-metabolism.
Our data suggest that OAC treatment may decrease local
expression of MGP, resulting in decreased circulating MGP
levels and subsequently increased aortic valve
calcifications as an adverse side effect.
PMID: 19350115
24
Relation of oral anticoagulation to cardiac valvular and
coronary calcium assessed by multislice spiral computed
tomography.
Am J Cardiol. 2005 Sep 15;96(6):747-9.
Patients with long-term oral anticoagulation therapy
(mean duration 88 +/- 113 months) were compared
with those without anticoagulation .
The results of our study have demonstrated that oral
anticoagulation may be associated with increased
valvular and coronary calcium in patients with aortic
valve disease, presumably due to decreased
activation of the matrix Gla protein.
PMID: 16169351
25
Long-term oral anticoagulation reduces bone mass in
patients with previous hemispheric infarction and
nonrheumatic atrial fibrillation.
Stroke. 1997 Dec;28(12):2390-4
CONCLUSIONS: Bone mineral density was significantly
lower in stroke patients with long-term warfarin
treatment than in untreated patients.
Both warfarin-induced reduction in vitamin K function
and lowered vitamin K1 concentrations are probable
causes of this osteopenia.
PMID: 9412619
26
A high menaquinone intake reduces the
incidence of coronary heart disease.
Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10
To examine the relationship between dietary vitamins K(1) and
K(2) intake, and its subtypes (MK-7, MK-8, MK-9), and the incidence
of CHD.
We used data from the Prospect-EPIC cohort consisting of
16,057 women, enrolled between 1993 and 1997 and aged 49-
70 years, who were free of cardiovascular diseases at baseline.
we observed an inverse association between vitamin K(2) and risk
of CHD
Vitamin K(1) intake was not significantly related to CHD
CONCLUSIONS: A high intake of menoquinones, especially MK-7,
MK-8 and MK-9, could protect against CHD.
PMID: 19179058
27
Dietary intake of menaquinone is associated with a
reduced risk of coronary heart disease:
the Rotterdam Study.
J Nutr. 2004 Nov;134(11):3100-5.
4807 subjects (over 10 year period) with dietary data and
no history of myocardial infarction at baseline (1990-1993)
Examined dietary intake of phylloquinone (vitamin K-1)
and menaquinone (vitamin K-2)
Dietary intake of menaquinone was inversely related to
CHD and all-cause mortality (50% reduction). Phylloquinone
intake was not.
These findings suggest that an adequate intake of
menaquinone could be important for CHD prevention.
PMID: 15514282
28
High dietary menaquinone intake is associated with
reduced coronary calcification.
Atherosclerosis. 2009 Apr;203(2):489-93.
Cross-sectional study among 564 post-menopausal
women (62% had coronary calcification)
CONCLUSION: This study shows that high dietary
menaquinone intake, but probably not phylloquinone,
is associated with reduced coronary calcification.
Adequate menaquinone intakes could therefore be
important to prevent cardiovascular disease.
PMID: 18722618
29
Vitamin K supplementation can improve stability of
anticoagulation for patients with unexplained variability in
response to warfarin.
Blood. 2007 Mar 15;109(6):2419-23.
Patients receiving warfarin who have unstable control of
anticoagulation have a significantly lower intake of dietary
vitamin K compared with their stable counterparts.
70 warfarin-treated patients with unstable anticoagulation
control
randomly assigned double-blinded 150 mcg oral vitamin K or
placebo orally for 6 months
Anticoagulation control improved in 33 of 35 patients receiving
vitamin K supplementation
Concomitant supplementation of vitamin K, perhaps through
reducing the relative day-to-day variability in dietary vitamin K
intake, can significantly improve anticoagulation control in
patients with unexplained instability of response to warfarin.
PMID: 17110451
30
Vitamin Kcontaining dietary supplements: comparison of
synthetic vitamin K 1 and natto-derived menaquinone-7
we propose to use an upper safety limit for intake of 50
mcg/d for long-chain menaquinones (including MK-7) in
patients on oral anticoagulant treatment.
This dose is comparable with the menaquinone content
of 75 to 100 g of cheese; such amount would lead to a
disturbance of the INR value of no more than 10%, which
may be regarded as tolerable in the management of
oral anticoagulant therapy.
On the other hand, its long half-life time suggests that
regular intake of MK-7 in combination with properly
adapted coumarin doses may result in more stable INR
values.
Blood. 2007;109:3279-3283
31
32
33
34
K2 vs. K1
Human studies show that vitamin K2 is up to ten times more bioavailable
than is K1.
Vitamin K2 remains biologically active in the body far longer than K1.
For instance, K1 is rapidly cleared by the liver within eight hours,
whereas measurable levels of K2 have been detected 72 hours after
ingestion.
Animal studies suggest vitamin K intake not only blocks the progress of
further calcium accumulation but also induces 37% regression of
preformed arterial calcification.
1,2
Low-Dose Vitamin K2 contains the menaquinone-7 form of vitamin K2,
which is not metabolized quickly by the liver, thereby making it available to
provide a more consistent supply of vitamin K to the body.
1. Spronk et al. J Vasc Res 2003;40:531
2. Schurgers et al. Blood 2007;109:2823
35
36
45 mcg K2
.
37
Best Support
Counsel patient on importance of consistent
dosing of vitamin k.
Consider use of K2 Menaquinone 7
45 mcg/d
Monitor therapy if adding or removing any dietary
supplements
38
39
Aspirin
Nutrient Depletions
Vitamin C: most likely to deplete in normal individuals
Iron: due to blood loss in GI tract
Folic acid: displaces bound serum folate
Potassium: increased urinary loss
Zinc: increased urinary loss
1. Loh HS, et al, The effects of aspirin on the metabolic availability of ascorbic acid in human
beings, J Clin Pharmacol. 1973; 13(11): 480-6.
2. Lawrence VA, et al, Aspirin and folate binding in vivo and in vitro studies of serum binding
and urinary excretion of endogenous folate, J Lab Clin Med. 1984; 103(6): 944-8.
3. Nain, et al. Acetylsalicylic acid-induced biochemical changes in gastric juice, Indian J
Gastroenterol. 1996; 56: 421-29.
4. Ambanelli U, Ferraccioli GF, Serventi G, Vaona GL. Changes in serum and urinary
zinc induced by ASA and indomethacin. Scand J Rheumatol 1982;11:634
40
The protective effect of liquorice components and
their derivatives against gastric ulcer induced by
aspirin in rats.
Aspirin coated with liquorice reduced the number
and size of ulcers reducing the ulcer index from
1.5 +/- 0.12 to 0.5 +/- 0.12 and the incidence from
96% to 46%.
Coating with derivatives was less effective (ulcer
index, 0.70-0.94; incidence 62-76%).
Dehpour AR, Zolfaghari ME, Samadian T, Vahedi Y. J Pharm
Pharmacol. 1994 Feb;46(2):148-9.
41
Effect of deglycyrrhizinated liquorice on
gastric mucosal damage by aspirin.
Gastric mucosal damage induced by giving 60 mg
aspirin orally to rats was reduced by simultaneous
administration of 100-500 mg deglycyrrhizinated
liquorice.
Human faecal blood loss induced by 975 mg aspirin
orally three times a day was less when 350 mg
deglycyrrhizinated liquorice was given with each dose
of aspirin.
Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A.
Scand J Gastroenterol. 1979;14(5):605-7.
42
Best Support
Optimal ranges of Vitamin C
Optimal level multivitamin-mineral formula for folic
acid and zinc plus their cofactors
Check iron and add if blood loss
Assure a healthy potassium diet
Enteric coated
DGL chewable at least 350 mg with each dose
aspirin
43
Inotropic Agents-
(Cardiac Glycosides)
DIGOXIN (LANOXIN, LANOXICAPS, DIGITEK) known as digitalis
Mechanism of action
Increases strength of heart muscle contractions
Makes heart rhythm more regular
Increases left ventricular ejection fraction
INDICATION: mild to moderate heart failure and atrial fibrillation
CONTRAINDICATION: Ventricular fibrillation, hypersensitivity to digitalis
preparations
WARNINGS/PRECAUTIONS: AV block (atrioventricular block), Sinus node
disease/dysfunction, acute myocardial infarction (heart attack), thyroid
disorders, electrolyte imbalances, malnutrition (elderly), moderate to
severe vomiting and diarrhea, impaired renal function.
SIDE EFFECTS: Digitalis toxicity, heart rhythm disturbances, visual
disturbances, headache, mental disturbances, nausea, vomiting, diarrhea,
gynecomastia, weakness, dizziness.
44
Inotropic Agents-
(Cardiac Glycosides)
Nutrient Depletions
Digoxin (Lanoxin)
Calcium, magnesium, phosphorus via increased
urinary excretion
Magnesium deficiencies increase likelihood of
cardiac dysrhythmias and atrial fibrillation
1. Crippa, et al. Magnesium and cardiovascular drugs: interactions
and therapeutic role, Ann Ital Med Int. 1999; 14: 40-45.
2. Kupfer S, et al. Effects of cardiac glycosides on renal tubular
transport of calcium, magnesium, inorganic phosphate and glucose
in the dog, J Clin Investig. 1965; 44: 1143.
45
Heart failure and electrolyte
disturbances.
Methods Find Exp Clin Pharmacol. 1992 May;14(4):315-25.
Digoxin directly limits the renal tubular reabsorption of
magnesium, therefore increasing magnesium
excretion.
Low magnesium and potassium concentrations
increase cardiac glycoside toxicity.
In contrast, elevated levels of magnesium decrease
the sensitivity of human myocardium to
antiarrhythmogenic actions of cardiac glycosides.
PMID: 1507935
46
Furosemide and digoxin inhibit thiamine
uptake in cardiac cells.
Eur J Pharmacol. 1998 Nov 13;361(1):151-5.
Thiamine uptake by cardiac cells grown in a thiamine-
free medium for 7 days decreased significantly in the
presence of furosemide or digoxin.
Our results demonstrate that furosemide and digoxin
inhibit thiamine uptake by cardiac cells in culture and
may therefore cause thiamine deficiency in patients
undergoing chronic treatment with these drugs.
PMID: 9851552
47
Best Support
Gender and Age specific Multivitamin mineral
thiamine works with other B vitamins in energy production;
studies show 80-240 mg per day improved ejection fraction
13 to 22 percent in CHF
Magnesium is required in the conversion of thiamine to its
active form
Consider optimal magnesium range from 6-12 mg/kg
Increase potassium in diet (no high dose in pill form)
Daily dietary requirements are 3600-5800 mg.
banana contains ~440 mg (thats a lot of bananas)
Can lose 3000 mg in one day of sweating
Multiple food choices provide better chance of patient
compliance-provide patient with potassium food chart
Address low gastric acid for mineral and b vitamin absorption
gastric acid is required for thiamine absorption and
thiamine helps produce stomach acid
Alcohol depletes thiamine
48
Calcium Channel Blockers
(Calcium Antagonist)
MECHANISM OF ACTION: They disrupt the calcium conduction of calcium
channels by inhibiting the movement of calcium ions across cell membranes of
the heart and blood vessels.
INDICATIONS: Hypertension, pulmonary hypertension, angina, arrhythmias,
migraines Raynauds, disease, brain aneurysm.
CONTRAINDICATIONS: Hypersensitivity to drug, ventricular arrhythmias, acute MI,
severe hypotension, cardiogenic block, atrial fibrillation or flutter, ventricular
tachycardia, second or third degree AV block.
WARNING/PRECAUTIONS: Hypotension, premature ventricular contraction,
hypertropic cardiomyophathy, antiplatelet effects, withdrawal syndrome,
impaired renal function, increased angina, children (safety and efficacy not
established.
SIDE EFFECTS: Constipation, peripheral edema, headache, tachycardia, rash,
drowsiness, flushing, dry mouth, dyspepsia, nausea.
49
Amlodipine (Norvasc)
Felodipine (Plendil)
Nicardipine (Cardene, Cardene SR)
Nifedipine (Procardia, Adalat)
Nisoldipine (Sular)
Verapamil (Calan, Isoptin) also SR and ER
Diltiazem( Cardiazem) also SR, ER, LA
Calcium Channel Blockers
(Calcium Antagonist)
NUTRIENTS DEPLETED
Copper: Based on human study, a lower concentration of
copper was found in red blood cells after use of nifedipine.
Melatonin: Based on human study, verapamil may
enhance excretion of melatonin.
Potassium
1. Misiewicz A, Jele B, Dziewit T, Radwan K, Srodo-Sikora I. Levels of copper, zinc and vitamin C in erythrocytes
of humans taking nifedipine. Pol Arch Med Wewn. 1998 May;99(5):398-402. PMID 9816889
2. Wikner J, Wetterberg L, Rjdmark S., Does hypercalcaemia or calcium antagonism affect human melatonin
secretion or renal excretion? Eur J Clin Invest. 1997 May;27(5):374-9. PMID 9179543
3. Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost of Prescription
Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004, 15.
50
Levels of copper, zinc and vitamin C in
erythrocytes of humans taking nifedipine
Pol Arch Med Wewn. 1998 May;99(5):398-402.
In red blood cells of men which take nifedipine in daily
doses 30 mg was found: lower copper concentration,
higher zinc concentration as compared to before
administration of nifedipine.
Changes in Cu and Zn blood concentrations were
intensified during administration of the drug. The
vitamin C concentration did not change substantially.
PMID: 9816889
51
Best Support
Melatonin if quality of sleep affected
Improve dietary potassium
Assure healthy zinc to copper ratio (multi-vitamin-
mineral)
High zinc or vitamin C decreases copper
Copper deficiency can elevate LDL and reduce
HDL while increasing risk of blood vessel
damage/rupture by decreasing the enzyme (lysyl
oxidase) required in cross linking of collagen.
Wilsons disease should never take copper
52
Vasodilators
NITRATES
Amyl nitrate
Nitroglycerine (Lingual spray, sub-lingual tabs, extended-release tabs,
ointment, transdermal patch)
Isosorbide dinitrate (immediate release)
Isosorbide monohydrate (extended-release)
Hydralazine
MECHANISM OF ACTION:
Relaxation of vascular smooth muscle
Dilation of peripheral arties and veins
INDICATION: Angina pectoris (acute and chronic)
CONTRAINDICATION: Glaucoma, pregnancy, cerebral hemorrhage,
hypersensitivity to nitrates
WARNINGS/PRECAUTIONS: Postural or severe hypotension, hypertropic
cardiomyophathy, withdrawal, tolerance.
SIDE EFFECTS: Headache, flushing, dizziness, nausea, rash, hives, itching,
paraesthesia, difficult breathing, chest tightness, swelling of mouth, face, lips, or
tongue, visual changes, numbness of arm and legs, crushing chest pain, sudden
leg pain, hypotension
53
Vasodilators
Nutrients Depleted
Coenzyme Q10
Magnesium
Vitamin B6 (Pyridoxine)
1. Raskin, NH.and Rishman, RA. Pyridoxine-deficiency neuropathy due to
hydralazine. New Eng. J. Med. 273:1182-1185, 1965.
2. Roe, D.A. Diet and Drug Interactions. New York, Van Nostrand Reinhold, p.
150, 1989.
54
Best Support
Gender and Age specific Multivitamin mineral
Optimal magnesium range from 6-12 mg/kg
COQ10 (ubiquinone)
in those that are under 50, or with no diabetes or
kidney health problems
assure the ubiquinone is 100% bio-identical and
proof of cellular mitochondrial absorption
Others will use ubiquinol (QH)
Aging, genetics and certain health concerns
(glycemic control, kidney damage, liver, or aging)
reduce the process where ubiquinone is converted
to ubiquinol (reduced form)
Low gastric acid will interfere with nutrient absorption
(minerals and B vitamins)
55
QH to Q10 to QH
Optimal health is 97% ubiquinol (QH) and 3%
ubiquinone (Q10)
Ubiquinone - oxidized form
Ubiquinol- reduced form
QH (ubiquinol) gives electron up in presence of free
radical
Enzyme reaction converts COQ10 ubiquinone back to
QH (ubiquinol)
enzyme reaction deficient in
aged
genetics (NQ01 gene)
health problems (i.e. diabetics, kidney or liver
disease)
56
Diuretics
TYPES:
THIAZIDE DIURETICS (Hydrochlorothiazide, Chlorothiazide, Indapamide, Chlorthalidone,
Metolazone.)
LOOP DIURETICS (Furosemide, Torsemide, Bumetanide, Ethacrynic Acid)
POTASSIUM SPARING DIURETICS (Spironolactone, Triamterene, Amiloride)
OSMOTIC DIURETICS (Mannitol, Glycerin)
MECHANISM OF ACTION:
Thiazides: inhibits the reabsorption of sodium and chloride ions from the
distal convoluted tubles in the kidney. Cause a net decrease of
calcium lost in the urine.
Loops: inhibits the reabsorption of sodium at the ascending loop of
henle in the kidney. Cause a significant increase calcium excretion.
Potassium Sparing: prevent the loss of potassium in the urine.
Osmotic: Increase the osmolarity of the filtrate and water is retained in
the urine.
INDICATIONS: Edema, congestive heart failure, liver cirrhosis, kidney
disease (stones), female hirsutism(spironolactone), hypokalemia
(spironolactone).
57
Diuretics (cont.)
TYPES:
THIAZIDE DIURETICS (Hydrochlorothiazide, Chlorothiazide, Indapamide,
Chlorthalidone, Metolazone.)
LOOP DIURETICS (Furosemide, Torsemide, Bumetanide, Ethacrynic Acid)
POTASSIUM SPARING DIURETICS (Spironolactone, Triamterene, Amiloride)
OSMOTIC DIURETICS (Mannitol, Glycerin)
CONTRAINDICATIONS: Anuria, renal impairment, hypersensitivity to any diuretic.
WARNING/PRECAUTIONS: Renal function impairment, hypersensitivity
reactions, dehydration, hepatic cirrhosis, tinnitus, electrolyte imbalances,
hypokalemia, hypomagnesemia, hypocalcemia, hyperuricemia, irregular
heartbeat.
SIDE EFFECTS: Hypovolemia (lassitude, thirst, muscle cramps, hypotension),
hypokalemia (muscle weakness, paralysis, arrhythmia), hyperkalemia
(arrhythmia, muscle cramps, paralysis), hyponatremia (CNS symptoms,
coma), Metabolic alkalosis (arrhythmia, CNS symptoms), metabolic
acidosis (muscle weakness, lethargy, coma, seizures, stupor),
hypercalcemia (gout, tissue calcification, fatigue, depression, confusion,
anorexia nausea, vomiting, constipation, pancreatitis, increased urination),
hyperuricemia (gout).
58
Potassium-Sparing Diuretics-
Drug Nutrient Interactions
Magnesium- Magnesium tends to be preserved.
Amiloride, Aldactone

(spironolactone),
Dytac

(triamterene)
1. Devane J, Ryan MP. The effects of amiloride and triameterene on urinary magnesium excretion in
conscious saline-loaded rats. Br J Pharmacol 1981;72:285-89
59
Potassium-Sparing Diuretics
Nutrients Depleted
Calcium
Zinc
Folic Acid
1. Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost of
Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004, 15.
60
Loop Diuretics
Nutrients Depleted
1
Calcium
Magnesium
Potassium
Zinc
Thiamine
Vitamin B6
Vitamin C
Loop diuretics increase Mg excretion and inhibit passive Mg
absorption.
2
1. Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional
Cost of Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company;
2004, 15.
2. Quamme GA, Renal magnesium handling: new insights in understanding old
problems. Kidney Int. 1997; 52(5): 1180-95.
61
Thiazide Diuretics
Nutrients Depleted
Magnesium
Potassium
Zinc
COQ10
Folic acid - increase homocysteine*
Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost of
Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004, 15.
Pelton R. LaValle JB Drug Induced Nutrient Depletion Handbook 2
nd
Edition
* South Med J. 1999 Sep;92(9):866-70. PMID: 10498160
62
Long-term diuretic therapy in hypertensive patients: effects on
serum homocysteine, vitamin B6, vitamin B12, and red blood cell
folate concentrations.
South Med J. 1999 Sep;92(9):866-70.
CONCLUSIONS: Chronic diuretic use is associated
with a significant increase in serum homocysteine
concentration, a significant decrease in RBC
folate concentration, and no significant change
in concentrations of vitamins B6 and B12.
PMID: 10498160
63
Diuretic-associated hypomagnesemia in
the elderly.
Arch Intern Med. 1987 Oct;147(10):1768-71.
Serum magnesium concentration- 320 consecutive
elderly patients (mean age, 81 years) receiving
diuretic therapy at the time of hospital admission.
When compared with serum concentrations of 250
elderly patients who were not taking diuretics at the
time of hospital admission, only the group taking
thiazide diuretics had a significantly reduced mean
serum level.
Patients taking therapy that included a potassium-
sparing diuretic had no significant evidence of
reduced magnesium-conserving ability.
PMID: 3662705
64
Thiazide treatment of systemic hypertension: effects
on serum magnesium and ventricular ectopic activity.
Am J Cardiol. 1989 Apr 18;63(14):22G-25G.
Potassium supplementation does not effectively
restore electrolyte balance unless accompanied by
magnesium.
Therefore, concomitant administration of potassium
and magnesium supplementation appears to be an
approach to reducing the risk of arrhythmias and
death in thiazide-treated hypertensive patients.
PMID: 2705372
65
Miscellaneous Diuretics
Indapamide, Metolazone, Chlorthialdone
Nutrients Depleted
Magnesium
Potassium
Zinc
Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost of
Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004, 15.
Pelton R. LaValle JB Drug Induced Nutrient Depletion Handbook 2
nd
Edition
66
Drugs and folate metabolism.
Drugs. 1985 Aug;30(2):145-55.
Triamterene acts as a folate antagonists and
produces folate deficiency by inhibiting the
enzyme dihydrofolate reductase.
PMID: 3896745
67
Best Support
Due to the multiple depletions of daily essential vitamins and
minerals an Optimal multi vitamin mineral is recommended.
Optimal magnesium range from 6-12 mg/kg
Optimal Vitamin C
Check homocysteine- (folic acid)
COQ10 (ubiquinone)
in those that are under 50, or with no diabetes or kidney
health problems.
assure the ubiquinone is 100% bio-identical and proof of
cellular mitochondrial absorption
Others will use ubiquinol (QH)
Aging, genetics and certain health concerns (glycemic
control, kidney damage, liver, or aging) reduce the process
where ubiquinone is converted to ubiquinol (reduced form)
Low gastric acid will interfere with nutrient absorption (minerals
and B vitamins)
68
Antiadrenergics/Sympatholytic Agents-
BETA-Adrenergic Blocking Agent
MECHANISM OF ACTION: Block the beta receptors in the heart which slows the
heart rhythm down.
INDICATIONS: Hypertension, angina, cardiac arrhythmias, MI, CHF, ventricular
tachycardia, migraines.
CONTRAINDICATIONS: Sinus bradycardia, sick sinus syndrome, shock, asthma,
hypersensitivity to the drug.
WARNINGS/PRECAUTIONS : Proarrhythmia, cardia failure, abrupt withdrawal,
peripheral vascular disease, nonallergic bronchospasms, bradycardia,
diabetes/hypoglycemia, electrolyte disturbances, hypotension, renal/hepatic
impairment, category D, lactation (in breast milk), children.
SIDE EFFECTS : Bradycardia, ventricular arrhythmias, dizziness, vertigo, tiredness,
fatigue, nightmares, rash, sweating, alopecia, psoriasis, acne, eczema, gas,
constipation, nausea, diarrhea, dry mouth, heartburn, impotence, decreased
libido, joint pain, muscle cramps, bronchospasms, cough, wheezing, nasal
stuffiness
69
ATENOLOL (TENORMIN)
BISOPROLOL (ZEBATA)
PINDOLOL (VISKEN)
SOTOLOL(BETAPACE)
ACEBUTOLOL (SECTRAL)
NADOLOL (CORGARD)
PROPRANOLOL (INDERAL & LA)
LOBETALOL (TRANDATE)
CARVEDILOL (COREG & CR)
METOPROLOL (LOPRESSOR, TOPROL XL)
Antiadrenergics/Sympatholytic Agents-
BETA-Adrenergic Blocking Agent
Nutrients Depleted
COQ10
Melatonin
1. Folkers, K. Basic chemical research on coenzyme Q-10 and integrated clinical research on
therapy of diseases, in Coenzyme Q, G. Lenaz, ed. John Wiley & Sons, 1985.
2. Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost of
Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004, 15.
70
Bioenergetics in clinical medicine XV. Inhibition of coenzyme
Q10-enzymes by clinically used adrenergic blockers of beta-
receptors.
Res Commun Chem Pathol Pharmacol. 1977 May;17(1):157-64.
Propranolol is frequently used to treat hypertension; in
some patients, it depresses myocardial function as an
adverse reaction.
This side effect may be related to the inhibition by
propranolol of CoQ10-enzymes of the myocardium.
PMID: 17892
71
Best Support
Melatonin - if sleep quality affected
COQ10 (ubiquinone)
in those that are under 50, or with no diabetes
or kidney health problems
assure the ubiquinone is 100% bio-identical and
proof of cellular mitochondrial absorption
Others will use ubiquinol (QH)
Aging, genetics and certain health concerns
(glycemic control, kidney damage, liver, or
aging) reduce the process where ubiquinone is
converted to ubiquinol (reduced form)
72
Renin Angiotensin System Antagonist-
Angiotensin-Converting Enzyme Inhibitors
(ACE Inhibitors)
BENZAPRIL (LOTENSIN)
CAPTOPRIL (CAPOTEN)
ENALAPRIL (VASOTEC)
FOSINOPRIL (MONOPRIL)
LISINOPRIL (PRINIVIL, ZESTRIL)
MOEXIPRIL (UNIVASC)
QUINAPRIL (ACCUPRIL)
RAMIPRIL (ALTACE)
MECHANISM OF ACTION: Blocks the angiotensin converting enzyme that
converts angiotensin I to angiotensin II in the kidney.
INDICATIONS: Hypertension, Congestive heart failure.
CONTRAINDICATIONS: Hypersensitivity to the drug
WARNINGS/PRECAUTIONS: Angioedema, anaphylactoid reactions,
proteinuria, hypotension, renal and hepatic impairment, category D (2
nd
and
3
rd
trimester), children (safety and efficacy not established), hypokalemia,
surgery/anesthesia, chronic cough, photosensitivity.
SIDE EFFECTS: Persistent dry cough, orthostatic hypotension, hypotension, renal
impairment, severe allergic reactions, hyperkalemia, dizziness, fatigue,
headache, nausea.
73
Renin Angiotensin System Antagonist-
Angiotensin-Converting Enzyme Inhibitors
(ACE Inhibitors)
NUTRIENTS DEPLETED
Na
Zinc
1. Pelton R. LaValle JB. The Quick Reference Guide to Nutrient Losses. In: The Nutritional Cost
of Prescription Drugs.2nd Edition Englewood, CO: Morton Publishing Company; 2004,
74
Zinc metabolism in patients treated with
captopril versus enalapril.
Metabolism. 1990 Jul;39(7):665-7.
We conclude that (1) although both captopril
and enalapril produce renal zinc loss, this loss is
far greater in patients receiving captopril; and (2)
captopril administration over 3 months or more
generates RBC zinc depletion.
PMID: 2195291
75
Effects of captopril and enalapril on zinc
metabolism in hypertensive patients.
Am Coll Nutr. 1998 Feb;17(1):75-8.
RESULTS: Significant enhancement of 24-hour
urinary zinc excretion (micrograms/24 hour) after
6 months of treatment was observed only in the
captopril-treated group (p < 0.01).
CONCLUSION: Treatment of hypertensive patients
with captopril or enalapril may result in zinc
deficiency.
PMID: 9477394
76
Best Support
Optimal multivitamin mineral for zinc
keep zinc and copper balanced
If Na depletion is a problem then address
Low gastric acid will interfere with nutrient
absorption (zinc)
77
Antiadrenergics/Sympatholytic Agents-
Angiotensin II Receptor Antagonist
(AT1-Receptor Antagonist)
LOSARTAN (COZAAR)
VALSARAN (DIOVAN)
IRBESARTAN (AVAPRO)
CANDESARTAN (ATACAND)
TELMISARTAN (MICARDIS)
OLMESARTAN (BENICAR)
ALISKIREN (TEKTURNA)
MECHANISM OF ACTION: Block the activation of angiotensin II AT1 receptor
INDICATIONS: Hypertension, Nephropathy in type 2 diabetics
CONTRAINDICATIONS: Hypersensitivity to the drug
WARNINGS/PRECAUTIONS: Hypotension, salt depleted patients, renal and
hepatic impairment, fertility impairment, category D (2
nd
and 3
rd
trimester),
children (safety and efficacy no established), potassium supplements,
creatinine/blood urea nitrogen, serum potassium.
SIDE EFFECTS: Dizziness, fatigue, diarrhea, heartburn, musculoskeletal pain,
upper respiratory tract infection, cough.
78
Antihyperlipidemic Agents-
HMG-CoA Reductase Inhibitor (Statins)
LOVASTATIN (MEVACOR, MEVINOLIN)
SIMVASTATIN (ZOCOR)
PRAVASTATIN (PRAVACHOL)
ROSUVASTATIN (CRESTOR)
FLUVASTATIN (LESCOL AND XL)
ATORVASTIN (LOPITOR)
MECHANISM OF ACTION: NEXT SLIDE (STATIN PATHWAY)
INDICATIONS:
Heterozygous familial hypercholesterolemia in adolescents
Homozygous familial hyperlipidemia
Hypertriglyceridemia
Mix dyslipidemia
Primary hypercholesterolemia
CONTRAINDICATIONS: Hypersensitivity to the drug
WARNINGS/PRECAUTIONS: Skeletal muscle effects (myopathy, rhabdomyolysis),
endocrine effects, hypersensitivity reactions, hepatic impairment, alcholics,
category X, lactation (in breast milk), liver enzymes.
SIDE EFFECTS: Asymptomatic serum transaminase increases, myalgia, back pain,
headache, abdominal pain, diarrhea, gas, nausea, vomiting, sinusitis, fatigue.
79
Antihyperlipidemic Agents-
HMG-CoA Reductase Inhibitor (Statins)
Nutrient Depletions
COQ10
Selenium
Zinc
Copper
Lowers serum fatty acid concentrations and alters the relative
% of PUFAs
1. Folkers K, et al. Lovastatin Decreases Coenzyme Q Levels in Humans, Proc Natl Acad Sci USA. 1990 Nov; 87(22):
8931-34.
2. Mortensen SA, et al. Dose-related Decrease of Serum Coenzyme Q10 during Treatment with HMG-CoA Reductase
Inhibitors, Mol Aspects Med. 1997; 18 Suppl: S137-44.
3. Ghirlanda G, et al. Evidence of Plasma CoQ10-lowering Effect by HMG-CoA Reductase Inhibitors: ADB PC Study, J
Clin Pharmacol. 1993 Mar; 33(3): 226-29.
4. Bargossi AM, Grossi G, Fiorella PL, et al. Exogenous CoQ10 supplementation prevents plaxma ubiquinone reduction
induced by HMG-CoA reductase inhibitors. Mol Aspects Med 1994;15(suppl):s187-93. Langsjoen PH,
5. Langsjoen, AM. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A
review of animal and human publications. Biofactors 2003;18 (1-4); 101-11.
80
Biosynthetic Pathway of Cholesterol
Acetyl CoA

HMG-CoA

-------- HMG-CoA Reductase

Mevalonic Acid

Coenzyme Q10 Farnesyl Pyrophosphate

Squalene

Cholesterol
81
Atorvastatin decreases the coenzyme Q10 level in the
blood of patients at risk for cardiovascular disease
and stroke.
Arch Neurol. 2004 Jun;61(6):889-92
A significant decrease was already detectable after 14 days of
treatment .
CONCLUSIONS: Even brief exposure to atorvastatin causes a
marked decrease in blood CoQ(10) concentration.
Widespread inhibition of CoQ(10) synthesis could explain the
most commonly reported adverse effects of statins, especially
exercise intolerance, myalgia, and myoglobinuria.
PMID: 15210526
82
Evidence of plasma CoQ10-lowering effect by HMG-
CoA reductase inhibitors: a double-blind, placebo-
controlled study.
J Clin Pharmacol. 1993 Mar;33(3):226-9
We studied two groups
5 healthy volunteers 20 mg/day of pravastatin or simvastatin for 1
month.
30 hyper-cholesterolemic patients with pravastatin, simvastatin (20
mg/day), or placebo for 3 months.
40% reduction (COQ10) after the treatment
CoQ10 is essential for the production of energy and also has
antioxidative properties. A diminution of CoQ10 availability may be
the cause of membrane alteration with consequent cellular damage.
PMID: 8463436
83
Lipid-lowering drugs and essential omega-6 and
omega-3 fatty acids in patients with coronary heart
disease.
Nutr Metab Cardiovasc Dis. 2005 Feb;15(1):36-41
Male patients with CHD and high cholesterol levels (double-blind
protocol) to receive either simvastatin 20mg (S) or fenofibrate
200mg daily (F) for 3 months.
LLDs significantly alter the metabolism of essential fatty acids that
are critically important for the pathogenesis and prevention of
CHD.
Further studies are urgently needed:
examine the effects of higher dosages
whether specific dietary intervention (combining low intake of n-6 fatty
acids and high intake of n-3 fatty acids) may improve the effectiveness of
these drugs
PMID: 15871849
84
Statin treatment alters serum n-3 and n-6 fatty
acids in hypercholesterolemic patients.
Prostaglandins Leukot Essent Fatty Acids. 2004 Oct;71(4):263-9
Subjects were 106 healthy adults with hypercholesterolemia
randomly assigned to receive placebo or 40 mg simvastatin
daily for 24 weeks.
Relative percentages of linoleic acid (LA, 18:2n-6) and alpha-
linolenic acid (LNA, 18:3n-3), decreased while AA and DHA
increased.
Thus, simvastatin lowered serum fatty acid concentrations
while also altering the relative percentages of important PUFAs.
PMID: 15310527
85
Statin-associated myopathy with normal
creatine kinase levels.
Ann Intern Med. 2002 Oct 1;137(7):581-5.
Creatine kinase levels were normal in all four patients
despite the presence of significant myopathy.
CONCLUSION: Some patients who develop muscle
symptoms while receiving statin therapy have
demonstrable weakness and histopathologic findings
of myopathy despite normal serum creatine kinase
levels.
PMID: 12353945
86
Association between statin-associated
myopathy and skeletal muscle damage.
CMAJ. 2009 Jul 7;181(1-2):E11-8.
Of the 44 patients with clinically diagnosed statin-associated
myopathy, 29 were currently taking a statin, and 15 had discontinued
statin therapy before the biopsy (minimal duration of discontinuation 3
weeks).
RESULTS: Muscle injury was observed in 25 (of 44) patients with
myopathy and in 1 patient without myopathy.
Only 1 patient with structural injury had a circulating level of creatine
phosphokinase that was elevated more than 1950 U/L (10x the upper
limit of normal).
A lack of elevated levels of circulating creatine phosphokinase does
not rule out structural muscle injury. Upregulation of the expression of
ryanodine receptor 3 is suggestive of an intracellular calcium leak.
PMID: 19581603
87
Best Support
Due to the multiple depletions (zinc, selenium, copper) use of a
daily essential vitamins and mineral formula is recommended.
COQ10 (ubiquinone)
in those that are under 50, or with no diabetes or kidney
health problems.
assure the ubiquinone is 100% bio-identical and proof of
cellular mitochondrial absorption
Others will use ubiquinol (QH)
Aging, genetics and certain health concerns (glycemic
control, kidney damage, liver, or aging) reduce the process
where ubiquinone is converted to ubiquinol (reduced form)
Low gastric acid will interfere with nutrient absorption (minerals)
Lower the omega 6 intake and increase omega 3s (natural
stable ratio fish oil)
88
Antihyperlipidemic Agents-
Fibric Acid Derivatives
Gemfibrozil (Lopid)
Femofibrate (Tricor, Triglide)
MECHANISM OF ACTION: Not definitely established.
Gemfibrozil inhibits peripheral lipolysis and decreases hepatic excretion of
free fatty acids.
Gemfibrozil inhibits synthesis and increases clearance of VLDL
(apolipoprotein B) leading to a decrease in VLDL.
INDICATIONS: Hypertriglyceridemia, Prevention of cardiovascular disease.
CONTRAINDICATIONS: Hypersensitivity to drug, hepatic or renal dysfunction,
WARNING/PRECAUTIONS: Gallstones, concomitant anticoagulants, skeletal
muscle effects, cataracts, renal and hepatic impairment, abnormal liver
functions children (safety and efficacy not established.)
SIDE EFFECTS: GI reactions (dyspepsia, abdominal pain, diarrhea, constipation,
nausea, vomiting).
89
Antihyperlipidemic Agents-
Fibric Acid Derivatives
Nutrient Depletions
COQ10
Vitamin E (alpha & gamma tocopherol)
B6, B12, Folic acid - Increases homocysteine
1. Aberg, et al. Gemfibrozil-induced decrease in serum ubiquinone and alpha- and gamma-
tocopherol levels in men with combined hyperlipidemia, Eur J Clin Invest. 1998; 28: 235-42.
90
The effect of fibrates and other lipid-lowering drugs on
plasma homocysteine levels.
Expert Opin Drug Saf. 2004 Mar;3(2):101-11.
fenofibrate and bezafibrate lead to a 20 - 40%
elevation of plasma levels of the atherogenic amino
acid homocysteine, thereby possibly counteracting
the desired cardiovascular protection
The increase of plasma homocysteine after
fenofibrate can be lowered by the concurrent
administration of folic acid and vitamins B(12) and
B(6). Thus, patients with hypertriglyceridaemia can
either be concurrently treated with fenofibrate and
vitamins (B6, folic acid, B12) or with gemfibrozil.
PMID: 15006716
91
Serum homocysteine increases after
therapy with fenofibrate or bezafibrate.
Lancet. 1999 Jul 17;354(9174):219-20.
A 44% and 17.5% increase of homocysteine
occurred in patients treated either with
fenofibrate or bezafibrate.
PMID: 10421307
92
Best Support
Mixed tocopherols vitamin E
Check homocysteine- Optimal b complex vitamins
COQ10 (ubiquinone)
in those that are under 50, or with no diabetes or
kidney health problems.
assure the ubiquinone is 100% bio-identical and
proof of cellular mitochondrial absorption
Others will use ubiquinol (QH)
Aging, genetics and certain health concerns
(glycemic control, kidney damage, liver, or aging)
reduce the process where ubiquinone is converted
to ubiquinol (reduced form)
Low gastric acid will interfere with nutrient absorption
(minerals and B vitamins)
93
Antihyperlipidemic Agents-
Bile Acid Sequestrants
COLESTIPOL (COLESTID)
CHOLESTYRAMUNE (QUESTRAN)
COLESEVELAM (WELCHOL)
MECHANISM OF ACTION: Bind bile acids in the intestines to form an
insoluble complex that is excreted in the feces. The increased fecal loss of
bile acid leads to increased oxidation of cholesterol to bile acids and a
decrease in LDL and serum cholesterol.
INDICATIONS: Hyperlipoproteinemia, biliary obstruction, clostridium difficle,
digitalis toxicity.
CONTRAINDICATIONS: Hypersensitivity to any drug, complete biliary
obstruction (Questran), bowel obstruction (Welchol).
WARNING/PRECAUTIONS: Phenylketonurics, lactation, children (Questran
only), thyroid function, malabsorption , reduced folate, GI disorders,
constipation.
SIDE EFFECTS: Abdominal discomfort, cramping, aggravating hemorrhoids,
blood in stool, constipation, diarrhea, intestinal gas, nausea, vomiting,
heartburn, indigestion.
94
Antihyperlipidcermic Agents-
Bile Acid Sequestrants
Nutrients Depleted
Vitamins A, D, E, K, B12
Calcium
Magnesium
Phosphorous
Zinc
Iron
Folic Acid
Beta-carotene
Fat
1. Roe, DA. Drug-Induced Nutritional Deficiencies. Second Edition. Westport, CT, Avi Publishing, pp.
158-159, 1985.
2. Hoppner & Lampi, Bioavailability of folate following ingestion of cholestyramine in the rat, Int J
Vitamin Nutr Res. 1991; 61: 130-4.
95
Best Support
Due to the multiple depletions of daily essential
vitamins and minerals an optimal multi vitamin
mineral is recommended.
96
NUTRIENT DEPLETIONS
CARDIOVASCULAR REFERENCES
DIGOXIN
PMID: 1507935, Heart failure and electrolyte disturbances.
PMID: 9851552, Furosemide and digoxin inhibit thiamine uptake in cardiac cells.
POTASSIUM
PMID: 4456986, Drug-induced malabsorption of vitamin B12. VII. Malabsorption of B12 treatment
with potassium citrate.
PMID: 5032681, Drug-induced malabsorption of vitamin B 12 . IV. Malabsorption and deficiency of B
12 during treatment with slow-release potassium chloride.
97
NUTRIENT DEPLETIONS
LIPID REDUCING DRUGS REFERENCES
FIBRATES
PMID: 15006716, The effects of fibrates and other lipid-lowering drug on plasma homocysteine
levels.
PMID: 11500187, Vitamin supplementation can markedly reduce the homocysteine elevation
induced by fenofibrate.
PMID: 12851616, Effect of folic acid on fenofibrate-induced elevation of homocysteine and
cysteine.
PMID: 11527658, Folate supplementation prevents plasma homocysteine increases after
fenofibrate therapy.
PMID: 12953339, Comparative effects of atorvastatin, simvastatin, and fenofibrate on serum
homocysteine levels in patients with primary hyperlipidemia.
PMID: 9568470, Gemfibrozil-induced decrease in serum ubiquinone and alpha and gamma
tocopherol levels in men with combined hyperlipidaemia.
PMID: 15019536, Serum homocysteine concentrations, gemfibrozil treatment, and progression of
coronary atherosclerosis.
PMID: 12534325, Fenofibrate-induced hyperhomocysteineaemia: Clinical implications and
management.
98
NUTRIENT DEPLETIONS
LIPID REDUCING DRUGS REFERENCES (cont.)
BILE ACID SEQUESTRANTS
PMID: 8660081, Low dose colestipol in adolescents with familial hypercholesterolaemia.
PMID: 40578, in vitro binding of various biological substances by two hypocholesterolaemic resins,
cholestyramine and colestipol.
PMID: 3881283, Metabolic mechanism of drug-nutrient interactions.
PMID: 1168607, The effect of cholestyramine on intestinal absorption.
PMID: 7627696, Probucol treatment decreases serum concentrations of diet-derived antioxidants.
PMID: 3547004, Adverse effects of hypolipidaemic drugs.
PMID: 3987479, Alterations in calcium, magnesium, and zinc metabolism by dietary
cholestyramine.
PMID: 7046936, Drug-nutrient interaction.
99
NUTRIENT DEPLETIONS
LIPID REDUCING DRUGS REFERENCES (cont.)
STATINS
PMID: 9266515, Dose-related decrease of serum Coenzyme Q10 during treatment with HMG-CoA
reductase inhibitors.
PMID: 17681347, Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver
and muscle enzyme levels in hypercholesterolemic patients treated with atrovastatin: A randomized
double-blind study.
PMID: 15942122, Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in
hypercholesterolemic patients.
PMID: 16872244, Effects of ezetimibe and/or simvastin on Coenzyme Q10 levels in plasma: A
randomized trial.
PMID: 8463436, Evidence of plasma CoQ10-lowering effects by HMG-CoA reductase inhibitors: A
double-blind, placebo-controlled study.
PMID: 14695926, Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting
other antioxidants and PUFA.
PMID: 7752830, Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction
induced by HMG-CoA reductase inhibitors.
100
NUTRIENT DEPLETIONS
LIPID REDUCING DRUGS REFERENCES (cont.)
STATINS (cont.)
PMID: 15210526, Atorvastatin decreases the Coenzyme Q10 levels in the blood of patients at risk for
cardiovascular disease and stroke.
PMID: 17493470, Effects of Coenzyme Q10 on myopathic symptoms in patients treated with statins.
PMID: 17610923, Reduced mitochondrial Coenzyme Q10 levels in HepG2 cells treated with high-
dose simvastin: A possible role in statin induced hepatotoxicity.
PMID: 15310527, Statin treatment alters Serum N-3 and N-6 fatty acids in hypercholesertolemic
patients.
PMID: 15031036, Selenoprotein synthesis and side-effects of statins.
PMID: 19203713, Fibrates but not statins increase plasma selenium in dyslipidemic aged patients
The EVA study.
PMID: 16240674: Effects of statin therapy on serum trace element status in dyslipidaemic subjects.
101
NUTRIENT DEPLETIONS ANTIHYPERTENSIVES/DIURETICS
REFERENCES
PMID: 9350641, Renal magnesium handling: new insights in understanding old problems.
PMID: 3193027, Is lymphocyte magnesium concentration a reflection of intracellular magnesium
concentration?
PMID: 16272623, Potassium and magnesium depletions in congestive heart failure--
pathophysiology, consequences and replenishment.
PMID: 8807629, Effect of furosemide oral solution versus furosemide tablets on diuresis and
electrolytes in patients with moderate congestive heart failure.
PMID: 7722187, Thiamin status, diuretic medications, and the management of congestive heart
failure.
PMID: 1867241, Thiamine deficiency in patients with congestive heart failure receiving long-term
furosemide therapy: a pilot study.
PMID: 9851552, Furosemide and digoxin inhibit thiamine uptake in cardiac cells.
PMID: 14712323, Thiamine deficiency in congestive heart failure patients receiving long term
furosemide therapy.
PMID: 7722187, Thiamin status, diuretic medications, and the management of congestive heart
failure.
PMID: 9820088, [The effect of furosemide on urinary excretion of oxalic acid, vitamin C and vitamin
B6 in chronic kidney failure].
102
NUTRIENT DEPLETIONS ANTIHYPERTENSIVES/DIURETICS
REFERENCES (cont.)
PMID: 10681666, Influence of water and sodium diuresis and furosemide on urinary excretion of
vitamin B(6), oxalic acid and vitamin C in chronic renal failure.
PMID: 9350682, Metabolism of vitamin B6 and its requirement in chronic renal failure.
PMID: 5588008, Studies of the effect of the diuretics furosemide, ethacrynic acid and triamterene
on renal magnesium and calcium excretion].
PMID: 3896745, Drugs and folate metabolism.
PMID: 3760669, Competitive inhibition of folic acid absorption in rat jejunum by triamterene.
PMID: 6635871, Urinary magnesium output after a single dose of indapamide in healthy adults.
PMID: 8750365, Ramipril decreases chlorthalidone-induced loss of magnesium and potassium in
hypertensive patients.
PMID: 1778085, Changes in blood pressure, serum potassium and electrolytes with a combination
of triamterene and a low dose of chlorthalidone.
PMID: 6376209, Chlorthalidone-triamterene: a potassium-sparing diuretic combination for the
treatment of oedema.
PMID: 2915738, Hypokalaemia in hypertensive patients treated with diuretics: no increase in
cardiac arrhythmias.
PMID: 17583180, Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine
levels.
103